The Fischer indole reaction provides a versatile and convergent route to a wide variety of indoles. However, when the ketone component of the reaction has two enolizable sites, regiocontrol is often a problem. In 1902 Plancher and Bonavia (Gazz. Chim. Ital. II, 32, 414 (1902)) published general rules governing the direction of indolization of unsymmetrical ketone arylhydrazones, the gist of which were that hydrazones made from methyl alkyl ketones A give 3-substituted-2-methylindoles B as the major products (eq. 1) and that dialkyl ketones give mixtures of products. ##STR2##
In the intervening years many examples have supported the conclusion that methyl alkyl ketones provide the 3-substituted-2-methylindoles B as the sole or major product (B. Robinson, "The Fischer Indole Synthesis," Wiley:New York, 1982, pp. 241-250).
F. A. Trofinov, et al. (Chem. Het. Comps., 15, 63 (1979) and citations therein) have disclosed that a thioether group may be used to direct the regiochemistry of the indolization and subsequently removed to provide the 3-unsubstituted indole.
H. Illy and L. Funderburk (J. Org. Chem., 11, 4283 (1968)) have disclosed studies in which they varied the strength of the acid catalysts employed in the reaction illustrated hereinbelow (D: R.sup.a =R.sup.b =H, R.sup.c =R.sup.d =CH.sub.3). They disclose that the greater ratio of compounds F:E are obtained when strongly acidic conditions are employed and the highest ratio was observed when 5 molar equivalents of polyphosphoric acid (PPA) were employed with toluene as a solvent. ##STR3##
M. H. Palmer and P. S. McIntyre (J. Chem. Soc. (B), 446 (1969)) have disclosed studies similar to Illy and Funderburk using various acid catalysts and several phenylhydrazones. They disclose that the 3-unsubstituted product is obtained exclusively when D (R.sup.a =R.sup.b =H, R.sup.c =R.sup.d =CH.sub.3) is reacted in 70% sulfuric acid in aqueous ethanol. When D (R.sup.a =R.sup.b =R.sup.c =H, R.sup.d =CH.sub.3) is reacted under similar conditions, the two products E and F are formed in equal amounts.
P. E. Eaton, et al. (J. Org. Chem., 23, 4071 (1973)) disclose a new reagent, a 1:10 by weight solution of phosphorous pentoxide in methane sulfonic acid which is an effective substitute for polyphosphoric acid. They cite greater ease of handling, increased solubility of organic compounds in the reagent and more convenient workup procedures as reasons for the attractiveness of the new reagent. They also state that in terms of relative rate, product distribution and yield, the new reagent mimics PPA in the selected examples they studied.
European Patent Application 166,591 and 275,667 disclose a series of indole-based compounds with activity as prostaglandin antagonists and inhibitors of leukotriene biosynthesis respectively.
A number of N-acyl derivatives of indole-3-acetic acid are described as potential anti-inflammatory agents by Biniecki, et al., Chem. Ab., Vol. 98, 197936 (1983), by Pakula, et al., Chem. Ab., Vol. 105, 190835 (1986), and in British Pat. Spec. 1,228,848.
It is an object of the instant invention to provide a improved process for the preparation of 3-unsubstituted indoles by a Fischer Indole reaction in the presence of a mixture of phosphorous pentoxide and methane sulfonic acid. It is also an object to provide a process wherein a co-solvent is optionally employed.
It is also an object of the instant invention to provide a process for the preparation of 3-unsubstituted indoles having increased product yield and regiochemical control, relative to processes known in the art and described hereinabove, in the case where the ketone component of the hydrazone has two enolizable sites.
It is a further object of the instant invention to provide a novel process for the preparation of 3-unsubstituted indoles which are utilized as intermediates in the syntheses of leukotriene biosynthesis inhibitors.